Origins of Obesity?

Energetics Research Could Provide Clues

Is obesity an adaptive response to poverty? Playmobil people explain in under a minute in this latest edition of Science in 60 Seconds.

In the summer of 2011, UAB researcher David Allison, Ph.D., often hiked up the Blue Trail of Oak Mountain State Park to Peavine Falls.

It turns out that he was starting a journey down an unconventional path.

Accompanied by postdocs, graduate students, family, and his dog, Gigi, Allison used the hikes to launch wide-ranging scientific give-and-takes, dreaming up hypothetical experiments and asking “what-if” questions about the origins of obesity.

In turn, those questions have led to one of UAB’s most unusual grants—an $8-million, five-year Transformative Research Award from the National Institutes of Health, the first ever for the university. These grants, the NIH says, target “exceptionally innovative” research projects that “tend to be inherently risky.” Loosely speaking, the funding enables researchers to gamble on big-payoff ideas.

Perception Is Everything

David Allison and his team hope to shed new light on America's obesity epidemic by examining the links among obesity, aging, and health disparities.The ambitious idea from Allison’s team proposes that an organism’s perception of its environment has the power to make the organism change how quickly it ages (even though it may not be aware it is doing so). Furthermore, perception of the environment could make an organism alter its efforts to seek food and store more of that food as energy—in the form of caches of nuts and berries for birds, for example, or body fat in humans and mice.

Body fat is a key term, because ultimately, this UAB-led research seeks to understand one of the great public health puzzles of the past 20 years—why America has seen an explosion in life-shortening obesity. In Alabama, one of the fattest states, a higher rate of obesity among poorer groups of people creates health disparities. Obesity also increases rates of some cancers.

These problems are a focus for the Office of Energetics in the UAB School of Public Health, which debuted in July 2011 and is headed by Allison, a psychologist who also serves as the school’s associate dean for science. Energetics research looks at why and how biological organisms acquire, store, and use metabolizable energy—which includes food and body fat.

But energetics is much more than obesity and physical activity. It’s a complex domain that affects many aspects of health, perhaps including aging. For proof, Allison describes three “really interesting observations” that helped to point his team toward its new research:

"Perception matters,” Allison says. “If you perceive yourself to be at the bottom of a social hierarchy, that may lead to more food intake and more deposition of energy as body fat.”

First, caloric restriction prolongs life in most species, especially rodents, Allison explains. Second, human obesity in developed societies is more common among people of lower socio-economic status. Finally, almost all species senesce, meaning “they age to a certain point, then lose function, and then they die,” Allison says. “It’s easy to understand why an organism dies because it got eaten by a lion or it starves to death. But why does an organism die of old age? That’s not at all clear.”

Clues and Calories

Allison’s team proposed its general theory to tie together those three observations, aided by a number of other clues about obesity, aging, and health disparities.

One clue came from fruit fly experiments by Scott Pletcher, Ph.D., an assistant professor of molecular and integrative physiology at the University of Michigan, who is also part of the UAB-led Transformative Research Award team. Fruit flies decrease their life spans if fed high-calorie food, and increase their life spans if fed low-calorie food. But Pletcher found that fly life spans were also shortened if they could just smell high-calorie food.

“In other words, they didn’t have to eat the food,” Allison explains. “They just had to sense it was there.”

Another clue about the power of perception comes from mice and rats living in groups. Lower-ranking animals gain the most weight. Similarly, birds near the bottom of the “pecking order” gain the most body fat or store the most nuts and berries.

“These observations suggest to us that perception matters,” Allison says. “If you perceive yourself to be at the bottom of a social hierarchy, that may lead to more food intake and more deposition of energy as body fat.”

Unusual Experiments

The UAB-led team is testing its hypothesis in seven bold experiments. Three will take place at UAB, and one each at the universities of Michigan, Minnesota, Florida, and Aberdeen, Scotland.

In Birmingham, Tim Nagy, Ph.D., vice chair for research in the Department of Nutrition Sciences, will look at life spans of mice receiving the same amount of food, but housed at two different temperatures—81 and 72 degree Fahrenheit. In prior experiments, Nagy has already shown that those 72-degree animals, which burn extra calories to produce body heat, fare much better than the 81-degree mice in a mouse model of prostate cancer.

Meanwhile, Inga Kadish, Ph.D., a UAB assistant professor of cell, developmental, and integrative biology, will examine whether inducing the hunger hormone ghrelin, which acts on the brain, will increase life span in animal models. Kadisha has already shown that increased ghrelin reduces brain pathology in a mouse model of Alzheimer’s disease.

Daniel Smith Jr., Ph.D., a biochemist and molecular geneticist in the Department of Nutrition Sciences, will learn if altered time perception will shorten or lengthen mouse life spans. Different groups of mice will spend their lives experiencing “days” of light and dark that are slightly shorter—22 hours—or slightly longer—26 hours—than normal days.

Experiments with animal models at the other universities will gauge the effects of food insecurity on life span. One of the most intriguing studies, conducted by Pletcher in Michigan, will let fruit flies smell vinegar at the same time that their diets change from high- to low-calorie foods, which is known to alter life span with just a short exposure. Later in their lives, the flies will again smell vinegar to see if it induces a life span change without any change in feeding. This mimics Pavlov’s classic conditioning experiment, where a bell rang as he offered meat to dogs. After some training, the bell alone made the dogs salivate.

These initial experiments will take three years. Other UAB researchers will then look into molecular mechanisms that may drive observed changes in life span.

In the end, Allison says, the “crazy ideas” discussed on the summer hikes could lead to crucial knowledge and potential solutions to help manage obesity—which could put countless patients on the path to longer, healthier lives.